This invention relates to novel compounds which can inhibit angiogenesis, i.e. which can inhibit the generation or maturation of new blood vessels. It is believed that said compounds may be beneficial in the treatment of a variety of diseases, such as neoplastic diseases and in particular cancer.
It is now widely accepted that blocking angiogenesis around tumours could be a viable way of treating cancer, possibly as an adjuvant treatment. This is also reflected in the large number of development projects and clinical trials with angiogenesis inhibitors with different inhibitory approaches. It is estimated that more than 300 drug candidates are currently in various stages of testing [Matter, DDT, 6, 1005-1024, 2001]. The formation of new blood vessels is a very complex process, which may be targeted in a number of different ways. The candidate drugs, hence, include metalloprotease inhibitors, inhibitors of vascular endothelial growth factor (VEGF) formation, inhibition of VEGF receptors, integrin antagonist, growth factor antibodies, etc.
Of particular interest for the present invention are VEGF receptor inhibitors, most particular VEGFR-2 (KDR) receptor inhibitors. The clinically most advanced VEGF receptor inhibitor is semaxanib from Sugen, which was recently discontinued in Phase III studies. Analogues of semaxanib, however, continue to be in development. Another VEGF receptor inhibitor in clinical trial is PTK-787 from Novartis which has recently entered Phase III studies. Bilodeau has reviewed such inhibitors in clinical trials in Expert Opin. Investig. Drugs., 11, 737-745, 2002.
WO 01/29009 and WO 01/58899 describe pyridine derivatives as inhibitors of the VEGF receptor tyrosine kinase and the VEGF-dependent cell proliferation.
WO 02/090346 describes phthalazine derivatives as inhibitors of the VEGF receptor tyrosine kinase with angiogenesis inhibiting activity.
WO 04/056806 teaches 2-(1-H-indazol-6-ylamino)-benzamide compounds as protein kinases inhibitors which may be useful for the treatment of ophthalmic diseases.
PCT publications WO 00/27819, WO 00/27820, WO 01/55114, WO 01/81311, WO 01/85671, WO 01/85691, WO 01/85715, WO 02/055501, WO 02/066470, WO 02/090349, WO 02/090352, WO 03/000678, WO 02/068406, WO 03/040101, and WO 03/040102 all teach anthranilic acid amide derivatives which include compounds of general structure A, their preparation and their use as VEGF receptor tyrosine kinase inhibitors for the treatment of diseases associated with VEGF-dependent cell proliferation.

The use of anthranilic acid amide derivatives for other therapeutic purposes have previously been disclosed in, e.g. U.S. Pat. No. 3,409,688 (analgesic, anti-inflammatory, antiulcer), and in EP 564,356 (angiotensin II antagonist).
PCT publications WO 02/06213 and WO 99/01426 teach substituted phenylamino benzhydroxamic acid derivatives which include compounds of general structure B as MEK inhibitors, pharmaceutical compositions and methods of use thereof.

U.S. Pat. No. 5,155,110 teaches hydroxamic acid derivatives having cyclooxygenase and 5-lipoxygenase inhibiting properties and pharmaceutical compositions for treating conditions advantageously affected by the inhibition. The reference fails to describe tyrosine kinase inhibitory activity of the hydroxamic acid ester derivatives disclosed.